Methadone

Overview

Methadone is a synthetic, long-acting μ-opioid receptor agonist with additional activity as an N-methyl-D-aspartate (NMDA) receptor antagonist and serotonin/norepinephrine reuptake inhibitor. These pharmacological properties contribute to its role in the treatment of opioid use disorder (OUD) and in selected cases of chronic severe pain.

Its unique pharmacokinetics — particularly a long and variable half-life (8–59 hours) versus a much shorter analgesic duration (4–8 hours) — make it effective for once-daily dosing in OUD. However, these same properties increase the risk of drug accumulation, respiratory depression, and cardiac arrhythmias (QT prolongation), necessitating specialist oversight and structured monitoring.

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Pharmacological Class and Formulations

• Class: Synthetic opioid; μ-opioid receptor agonist

• Formulations:

  • Oral solution (commonly 1 mg/mL, 2 mg/mL, 10 mg/mL concentrate)

  • Oral tablets (5 mg, 10 mg)

  • Parenteral injection (10 mg/mL, limited use)

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Mechanism of Action

1. μ-opioid receptor agonism → reduces opioid cravings and withdrawal, provides analgesia.

2. NMDA receptor antagonism → contributes to neuropathic pain relief, reduces opioid tolerance development.

3. Monoamine reuptake inhibition → enhances descending pain inhibition pathways.

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Pharmacokinetics

• Absorption: Well absorbed orally, bioavailability 70–90%.

• Distribution: High tissue binding, large volume of distribution.

• Metabolism: Hepatic, via CYP3A4, CYP2B6, CYP2D6.

• Elimination: Renal and fecal.

• Half-life: 8–59 hours (high interindividual variability).

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Clinical Indications

1. Opioid Use Disorder (OUD)

   • Used in opioid treatment programs as maintenance therapy or for supervised withdrawal.

   • Reduces cravings, withdrawal symptoms, and risk of relapse.

   • Decreases overdose mortality and improves social functioning.

2. Chronic Severe Pain

   • Considered when alternative long-acting opioids are inadequate.

   • Useful in neuropathic pain due to NMDA receptor antagonism.

   • Requires expertise due to nonlinear pharmacokinetics and accumulation risks.

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Contraindications

• Known hypersensitivity to methadone.

• Severe respiratory depression.

• Acute asthma attack.

• Paralytic ileus.

• Concomitant use of monoamine oxidase inhibitors (within 14 days).

• Caution in QT prolongation, severe hepatic impairment, and concurrent CNS depressant use.

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Precautions

• Cardiac: Monitor ECG for QT prolongation, particularly at doses >100 mg/day.

• Respiratory: High risk of respiratory depression, especially during initiation or titration.

• Drug interactions: CYP3A4 inducers reduce effect; inhibitors increase toxicity risk.

• Dependence and diversion: Controlled substance; structured dispensing required.

• Pregnancy: Used for OUD in pregnancy; prevents withdrawal-associated fetal risk, but neonatal abstinence syndrome is expected.

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Adverse Effects

Common

• Constipation

• Sweating

• Nausea, vomiting

• Drowsiness, dizziness

• Weight gain

Serious

• Respiratory depression

• QT prolongation and torsades de pointes

• Hypotension, syncope

• Seizures (rare)

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Drug Interactions

• CYP3A4, CYP2B6, CYP2D6 inhibitors (e.g., azole antifungals, macrolides, SSRIs): increase methadone levels.

• CYP inducers (e.g., rifampin, phenytoin, carbamazepine): decrease methadone efficacy.

• Other CNS depressants (benzodiazepines, alcohol): additive respiratory depression.

• QT-prolonging agents (amiodarone, certain antipsychotics): increased arrhythmia risk.

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Dosage

Opioid Use Disorder (Adults)

• Induction: Start 10–30 mg once daily, with close monitoring.

• Titration: Increase by 5–10 mg every 3–5 days until withdrawal and cravings are controlled.

• Maintenance: Typically 60–120 mg once daily; some patients require higher or lower doses.

• Important: Must be administered under supervision in certified treatment programs.

Chronic Pain (Adults)

• Opioid-naïve: Not recommended as initial therapy.

• Conversion from other opioids: Use extreme caution; equianalgesic tables vary, and conversions are nonlinear at higher doses.

• Typical starting dose: 2.5 mg orally every 8–12 hours.

• Titration: Increase no more often than every 5–7 days, individualized to effect and tolerability.

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Monitoring

• Baseline: ECG (QT interval), renal and liver function, full medication review.

• During therapy:

  • Reassess ECG after dose increases >100 mg/day or if risk factors present.

  • Monitor respiratory status, sedation, blood pressure.

  • For OUD: assess withdrawal symptoms, cravings, adherence, and signs of diversion.

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Patient Counseling Points

• Take methadone exactly as prescribed; do not adjust dose without supervision.

• Risk of overdose is greatest during the first two weeks of treatment.

• Avoid alcohol and sedative-hypnotics.

• Report palpitations, fainting, or severe dizziness (possible QT prolongation).

• Methadone can cause drowsiness — caution with driving and machinery.

• For women of childbearing age: discuss pregnancy and breastfeeding risks.